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Mitochondrial uncoupling (MIUN)is a process that uncouples mitochondrial oxidation from ATP synthesis. MIUM is mediated by proton influx across the mitochondrial inner membrane without passing through ATP synthase. MIUN occurs naturally in mammals, induced by mitochondrial uncoupler proteins, or UCPs. There are two major types of UCPs, UCP1 and other UCPs such as UCP2 and UCP3. UCP1 is primarily expressed in brown fat tissue (BAT), activation of which leads to rapidly conversion of fat calories (chemical energy) into heat for keeping body temperature. UCP2 is ubiquitously expressed in tissues including liver, brain, heart, and muscles. UCP2 activation leads to a mild MIUN, which not only increases metabolism and dissipates fat accumulation but also reduces mitochondrial ROS production due to its effect in mild reduction of mitochondrial membrane potential (MMP). UCP2 activation is a natural response to ROS elevation. MIUN thus provides effective means for burning excess fat calories, for consuming cellular metabolites otherwise used for cell proliferation, and for cell protection against oxidative stress.

MIUN can be induced by small-moleculemitochondrial uncouplers, which we named miuninsMito BioPharma has proprietary know-how and a platform for miunin development.We have successfully developed miunins that mimic the effect of UCP1 or UCP2/3. These miunins are patent protected and can potentially be used for treating a variety of diseases including type 2 diabetes (reducing hepatic fat accumulation and hepatic insulin resistance), NASH (reducing hepatic fat accumulation, sensitizing hepatic insulin resistance, reducing liver damage, preventing and reversing inflammation and fibrosis), hypercholesterolemia (reducing acetyl-CoA supply for cholesterol synthesis in liver), liver cancer, hepatic metastases from other types of cancers, and leukemia (consuming cellular metabolites essential for cell proliferation in cancer cells).

Mitochondrial uncoupling occurs naturally in mammals, induced by mitochondrial uncoupler proteins (UCPs), such as UCP1. Mitochondrial uncoupling can also be induced by chemical uncouplers, which are usually lipophilic weak acids functioning within the mitochondrial inner membrane. They exist between the de-protonated form (U) and protonated form (UH). Near the outer side of the membrane where proton concentration is high, uncouplers are protonated. The protonated uncouplers move to the matrix side, where they are deprotonated and release the protons to the mitochondrial matrix. As a result, as each acetyl-CoA is oxidized, few ATP are produced and most energy is dissipated as heat.

Currently Mito BioPharma is focusing on NASH and type 2 diabetes. The company has IND leads for NASH and type 2 diabetes. Moreover, potential leads are being developed for liver cancer and leukemia

The above figure illustrates mechanistically the processes of oxidative phosphorylation and MIUN induced by small miunins. Note in red-dotted box: miunins are lipophilic weak acids functioning within the mitochondrial inner membrane. They exist between the de-protonated form (U) and protonated form (UH). Near the outer side of the membrane where proton concentration is high, Miunins are protonated. The protonated miunins move to the matrix side by random movements, where they are deprotonated and the protons are released to the mitochondrial matrix. As a result, the energy derived from oxidation of fat (or other nutrients) are directly converted to heat rather than for ATP synthesis.